This is a first in human (FIH), Phase I/Ib, open-label, multi-center study of DFF332 as a single agent and in combination with Everolimus or Spartalizumab plus Taminadenant in patients with advanced clear cell renal cell carcinoma and other malignancies with HIF stabilizing mutations.

The study consists of two parts, dose escalation and dose expansion. The dose escalation part of the study will initially evaluate DFF332 single agent. Dose escalation groups receiving DFF332 in combination with Everolimus or DFF332 in combination with Spartalizumab plus Taminadenant will open after at least two dose levels of single agent DFF332 have been evaluated.

The dose expansion part of single agent will include two treatment arms: Arm1A will enroll ccRCC patients (age 18 yo or above) and Arm1B will enroll patients with malignancies harboring HIF stabilizing mutations (age 12 yo and above). These include the following:

• Malignancies with VHL mutations (e.g. Von Hippel-Lindau disease)
• Malignancies with FH mutations (e.g. Hereditary leiomyomatosis and renal cell carcinoma)
• Malignancies with mutations in SDHD, SDHAF2, SDHC, SDHB, SDHA (e.g. Hereditary paraganglioma and pheochromocytoma syndrome)
• Malignancies with EPAS1/HIF2A mutations
• Malignancies with ELOC/TCEB1 mutations

The expansion part of the combination therapies will enroll patients with ccRCC and include Arm2A (DFF332 with Everolimus) and Arm3A (DFF332 with Spartalizumab plus Taminadenant).

Inclusion Criteria:

1. Male and female ≥ 18 years of age For Arm 1B: Male and female of age ≥ 12 years of age
2. Histologically confirmed and documented clear cell renal cell carcinoma (ccRCC). Disease must be measurable as determined by RECIST v1.1.

   For Arm 1B: histologically confirmed and documented malignancies in the context of the following cancer predisposing syndromes/disorders or harboring somatic mutations on one of these genes:

   • Malignancies with VHL mutations (e.g. Von Hippel-Lindau disease)
   • Malignancies with FH mutations (e.g. Hereditary leiomyomatosis and renal cell carcinoma)
   • Malignancies with mutations in SDHD, SDHAF2, SDHC, SDHB, SDHA (e.g. Hereditary paraganglioma and pheochromocytoma syndrome)
   • Malignancies with EPAS1/HIF2A mutations
   • Malignancies with ELOC/TCEB1 mutations Note: Mutations must have been previously identified through local molecular assays.
3. Patient with unresectable, locally advanced or metastatic ccRCC with documented disease progression following all standard of care therapy, including PD-1/L1 checkpoint inhibitor and a VEGF targeted therapy as monotherapy or in combination.

   Escalation: No restriction on the number of prior treatments Expansion (with the exception of Arm 1B): Up to 3 prior lines of treatment for advanced/metastatic disease For Arm 1B: Patients must have either metastatic disease or locally advanced disease that is unresectable or that patients be unfit for resection or other treatment modalities. Patients must have received prior standard therapy appropriate for their tumor type and stage of disease, and have no available therapies of proven clinical benefit; or in the opinion of the investigator, would be unlikely to tolerate or derive clinically meaningful benefit from appropriate standard of care therapy.

4. For patients age ≥ 16 years: ECOG performance status ≤ 1 For patients age ≥ 12 and < 16 years: Lansky performance status ≥ 70

Exclusion Criteria:

1. History of seizure disorder & extrapyramidal (EPS) symptoms
2. Impaired cardiac function or clinically significant cardiac disease, including any of the following:
   • Clinically significant and/or uncontrolled heart disease such as congestive heart failure requiring treatment (NYHA Grade ≥ 2), uncontrolled hypertension
   • Patients with corrected QT using the Fridericia's correction (QTcF) > 470 msec for all patients on screening ECG or congenital long QT syndrome Acute myocardial infarction or unstable angina < 3 months prior to study entry
   • History of stroke or transient ischemic event requiring medical therapy
   • Concomitant clinically significant cardiac arrhythmias, e.g. sustained ventricular tachycardia, and clinically significant second or third degree AV block without a pacemaker
3. Treatment with any of the following anti-cancer therapies prior to the first dose of study treatment within the stated timeframes:
   1. ≤ 4 weeks for radiation therapy or limited field radiation for palliation within ≤ 2 weeks prior to the first dose of study treatment.
   2. ≤ 4 weeks or ≤ 5 half-lives (whichever is shorter) for chemotherapy or biological therapy (including monoclonal antibodies) or continuous or intermittent small molecule therapeutics or any other investigational agent.
   3. ≤ 6 weeks for cytotoxic agents with major delayed toxicities, such as nitrosourea and mitomycin C.
   4. ≤ 4 weeks for immuno-oncologic therapy, such as CTLA-4, PD-1, or PD-L1 antagonists.
   5. Patients who have undergone major surgery ≤ 4 weeks prior to first dose of study treatment or who have not recovered for the surgical procedure.
4. Patient previously treated with a HIF2α inhibitor.
5. Uncontrolled concurrent illness including, but not limited to, ongoing active infection, uncontrolled hypertension, active peptic ulcer disease or gastritis, active bleeding diatheses, including any Patient known to have evidence of acute or chronic hepatitis B, hepatitis C, human immunodeficency virus (HIV), or a psychiatric illness/social situation that in the investigator's opinion would limit compliance with study requirements or compromise the ability of the patient to give written informed consent. Patients with chronic HBV or HCV disease that is controlled under antiviral therapy are allowed in the expansion parts but not in the escalation parts.
6. Use of any live vaccines against infectious diseases within 4 weeks of initiation of study treatment.
7. Presence of Grade ≥ 2 toxicity according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAEv5.0), from prior cancer therapy with the exception of neuropathy (inclusion of patients with neuropathy of Grade 2 or less is permitted), ototoxicity, and alopecia.
8. Pregnant or nursing (lactating) women

Other protocol-defined inclusion/exclusion criteria may apply.